A recent study completed by the National Cancer Institute states that at least twenty percent of all cancer deaths are due to agents readily available in the environment. Describing mechanisms by which these agents act, and taking steps to eliminate or modify their activity offers one of the most promising means of controlling neoplastic disease. At least twenty percent of all environmental carcinogens must undergo activation via mixed-function oxidation prior to interacting with critical intracellular sites. More information than now exists must be obtained concerning regulation of the mixed-function oxidase system in living cells before steps may be taken to alter its activity in a rational manner to control chemical carcinogenesis. Evidence has been obtained indicating that metabolism of drugs and carcinogens via mixed-function oxidase system is intimately related to other metabolic events in intact cells such as the generation of reducing equivalents. Work outlined in this proposal is directed at developing and applying rigorous methods to the quantitative study of drug oxidation and carcinogen activation in whole organs and the interaction of these processes with important steps of intermediary metabolism. The combined application of directly monitoring the metabolism of drugs and carcinogens in intact perfused organs, the measurement of intracellular pigments in living cells, and the correlation of these changes with metabolites and enzymes in freeze-clamped tissues offers a unique and powerful approach to defining metabolic interactions of the mixed-function oxidase system. Data obtained in these studies will furnish basic information needed to understand factors which regulate mixed-function oxidation in intact cells which may ultimately be applied to designing means of reducing the hazard of chemical carcinogenesis.